In recent years, it is known that various lipid mediators such as eicosanoid, platelet activating factor (PAF) and lysophosphatidic acid (LPA) are produced by the activity of phospholipase from cell membranes. Moreover, sphingosine 1-phosphate (hereinafter abbreviated as S1P) is a lipid which is produced by metabolic turnover of sphingolipid, acts as a mediator for signal transduction and delivers various signals into cells. Firstly, it was reported that S1P may act as an intracellular second messenger, then, by intracellular microinjection of S1P, it was revealed that S1P has a biological action in cell. However, intracellular substance affected directly by S1P has never identified. On the other hand, the existence of five subtypes of S1P receptor in cell membranes has been disclosed recently and it is gradually proved that their physiological activities are via S1P receptor. Five subtypes of S1P receptor are called EDG (Endothelial differentiation gene)-1, 3, 5, 6 and 8, respectively. They as well as EDG-2, 4 and 7 which are LPA receptors are 7-transmembrane G protein-coupled receptor (GPCR) and are called EDG receptor family. These discoveries originate with a report which was reported by Hia et al. in 1990 that EDG-1 is an orphan receptor which is induced by Phorbol 12-myristate 13-acetate (PMA) in human umbilical vein endothelial cells (HUVEC).
S1P receptors to which S1P binds deliver signals into cells via G-protein-coupled receptors. Gs, Gi, Gq are known as G-proteins to which S1P receptor can couple, and it is considered that the receptor is responsible for an increase of cell proliferation, an induction of cell chemotaxis, adversely, a decrease of cell proliferation, or an inhibition of cell chemotaxis. Furthermore, since systems via ERK signal which active p42MAPK/ERK2 operate in the lower of G-protein, it has been known that S1P receptors deliver various signals.
Inhibition of migration of smooth muscle cell or cancer cell, regulation of blood pressure, platelet aggregation and so on are known as pharmacological action of S1P. Recently, it is revealed that S1P plays an important role for angiogenesis. It was reported by Menq-Jer Lee et al. that S1P induced cell survival, formation of adherens junctions, morphogenesis of microvascular in HUBEC (Cell 99, 301–312 (1999)). Moreover, they reported that, in vitro and in vivo, S1P has a synergetic effect with fibroblast growth factor (FGF) or vascular endothelial growth factor (VEGF) for angiosenesis. It was revealed by OK-Hee Lee et al. that S1P stimulated DNA synthesis and chemotactic motility of HUVECs in vitro, and S1P induced angiogenesis by itself in vivo (Biochem. Biophys. Res. Commun. 264, 743–750 (1999)). These results indicated that an induction of angiogenesis via S1P receptor is one of the biological actions of S1P in the body.
Recently, EDG-1 knock-out mice were prepared (Yujing Liu et al, J. Clin. Inves. 2000) and it is indicated that S1P induced angiogenesis is the action via EDG-1 because abnormal angiogenesis lead to embryonic lethality of the mice. Therefore, it is suggested that EDG-1 agonist is used as a treating agent for disease caused by anangioplasia. For example, it is used as an agent for treatment of peripheral arterial disease such as arteriosclerosis obliterans, thromboangiitis obliterans, Buerger's disease or diabetic neuropathy, varicosity such as hemorrhoid, anal fissure or fistula ani, dissecting aneurysm of the aorta, sepsis, angiitis, nephritis or pneumonia, moreover, for prevention and/or treatment of various edematous state caused by ischemia of various organ or increase of the blood permeability, for example, myocardial infarction, stroke, angina, DIC (Disseminated intravascular coagulation), pleuritis, congestive heart failure or multiple organ failure. Furthermore, because angiogenesis closely relates to osteogenesis, it is used a treating agent for abnormal bone metabolism, for example, osteoprosis. Furthermore, because it is indicated that EDG-1 may inhibit chemotaxis of vascular smooth muscle in knock-out mouse, EDG-1 agonist is used as an agent for prevention and/or treatment for arterial sclerosis. Furthermore, it is used as an agent for prevention and/or treatment for bedsore, burn, chronic ulcerative colitis or Crohn's disease. It is used as prognostic or preoperative activator of blood vessel in various organ transplant, for example, heart transplantation, renal transplantation, dermal graft or liver transplantation.
Because it was revealed that S1P is effective for bleomycin induced lung fibrosis in mice (ref. WO01/03739), it is used as an agent for prevention and/or treatment for pulmonary fibrosis, interstitial pneumonia, chronic hepatitis, liver cirrhosis, chronic renal failure or glomerular sclerosis.
Therefore, it is considered that EDG-1 agonist is used as an agent for prevention and/or treatment for peripheral arterial disease such as arteriosclerosis obliterans, thromboangiitis obliterans, Buerger's disease or diabetic neuropathy, sepsis, angiitis, nephritis, pneumonia, stroke, myocardial infarction, edematous state, atherosclerosis, varicosity such as hemorrhoid, anal fissure or fistula ani, dissecting aneurysm of the aorta, angina, DIC, pleuritis, congestive heart failure, multiple organ failure, bedsore, burn, chronic ulcerative colitis, Crohn's disease, heart transplantation, renal transplantation, dermal graft, liver transplantation, osteoporosis, pulmonary fibrosis, interstitial pneumonia, chronic hepatitis, liver cirrhosis, chronic renal failure, or glomerular sclerosis.
The existence of a compound having EDG-1 agonistic action has never known until today.
On the other hand, in the specification of EP791576, it is described that benzoic acid derivatives represented by formula (X)
[wherein R1X is hydrogene, alkyl having up to six carbon atoms or substituted phenyl;    PX and QX are independently oxygen, sulfur or a bond;    XX is oxygen, sulfur or —CONH—;    TX is ethylene, oxygen, sulfur or a bond;    YX is —COOH, —NHSO2R3X or —CONHSO2R3X;    wherein R2X is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano or alkyl or alkoxy;    ZX is —COOH, COR4X, —CO(CH2)pXCO2H, —O(CH2)pXCO2H, —S(CH2)pXCO2H, NO2, —CONHWXCO2H or —NHWXCO2H;    wherein R2X has the above mentioned meaning;    R3X is trifluoromethyl, alkyl or optionally substituted phenyl;    R4X is WXCO2H or alkyl;    pX is an integer from 0 to 5;    WX is phenylene, alkylene having up to 8 carbon atoms which is optionally substituted by alkyl or cycloalkyl each having up to 6 carbon atoms or —CO(CH2)qX— or —(CH2)qX—;    wherein qX is an integer from 0 to 5;    mX is an integer from 0 to 6;    nX is an integer from 0 to 4.]and salts thereof are used as inhibitor of luekotriene.
Moreover, in the specification of JP02-218654, it is described that benzoic acid derivatives represented by formula (Y)
[wherein RY is a group represented by formula
(wherein R1Y is hydrogen, C1–8 alkyl, C1–8 alkoxy, halogen or trifluoromethyl;    IY is an integer from 1 to 5;    AY is 4–10 membered carbocyclic ring or cyclic hetero ring;    YY is a group represented by formula—O—AlK—O—,—AlK—O—, or—AlK—(wherein AlK is C1–8 alkylene.);    BY is 4–10 membered mono-carbocyclic ring or mono-cyclic hetero ring;    R2Y is hydrogene, C1–4 alkyl, C1–4 alkoxy, halogen, trifluoromethyl or C2–5 alkanoyl;    mY is an integer from 1 to 4.);    ZY is a bond, C1–6 alkylene or C2–6 alkenylene;    R3Y is hydrogen, C1–4 alkyl, phenyl or C1–4 alkyl substituted by phenyl;    R4Y is hydrogen, C1–4 alkyl, C1–4 alkoxy, halogen, trifluoromethyl, hydroxy or nitro;    nY is an integer from 1 to 4.]and non-toxic salts thereof are used as reverse transcriptase inhibitor.